OVERALL ? PROJECT SUMMARY/ABSTRACT Viruses cause approximately 15% of human cancers. A viral etiology to a human cancer can have substantive consequences on its treatment and prevention. For example, many virally-caused human cancers express virally encoded products, which are potential targets for anti-viral, tumor-specific therapies. In addition, unique sets of cellular genes and pathways contribute to virally-associated cancers, many of which are currently being pursued as targets for anti-cancer therapies. This program project grant (PPG), now in its 40h year of continual funding, has two major objectives: to use molecular biology and genetics to elucidate the life cycles of and transformation by human tumor viruses and to translate this understanding into the identification of targets for specific anti-viral, anti-tumor therapies. The PPG has eight investigators who share these research goals in studying human tumor viruses in three different virus families: papillomaviruses, hepadnaviruses and herpesviruses. Together, these three families of viruses cause the vast majority of virally-associated human cancers. The PPG has been highly productive over the current funding period with 86 studies published of which over 25% involve two or more labs, reflecting on the strong synergies arising from the PPG. Our PPG has a unique organization in which each of five projects have two or more labs working together on a common theme in human tumor virology. Cross-fertilization of ideas and expertise between projects is fostered by having many of the eight investigators participating in multiple projects. This interactive and collaborative organization has been highly fruitful over the current funding period in several regards. Firstly, each project has been highly productive. Secondly, innovative new ideas and approaches have arisen many of which are now being used across multiple projects. Thirdly, the collaborative environment created by this PPG has spawned new interactions that have brought additional expertise to the PPG. Most important of these interactions are highly productive interactions with two new members of the PPG, Drs. Johannsen and Sherer, resulting in 12 joint publications with 6 other PPG members over the current funding period and resulting in their recruitment into Projects 3 and 5, and Projects 2, respectively. The specific themes of this PPG are: 1) to identify and characterize cellular genes that drive human papillomavirus-associated cancer and modulate viral infection; 2) to define the intracellular trafficking of components of human hepadnavirus during the viral life cycle; 3) to study the replication and inheritance of herpesviral genomes in relevant cell types using novel approaches for live cell imaging; 4) to characterize cellular and viral factors that regulate the switch from the latent to lytic viral state of Epstein Barr virus (EBV); and 5) to define drivers of EBV- associated carcinogenesis and develop novel approaches for treating these cancers and diseases caused by herpesviruses. Three cores provide expertise in A) administration, statistics and bioinformatics, B) instrumentation, microscopy and histology, and C) virus engineering and production.